Crohn's disease (CD) is a debilitating condition with no known cure. The precise cause(s) of CD remain undefined. Increasing evidence suggests that CD may be initiated by a dysregulated innate immune response against unknown antigens in a genetically-susceptible host. The central hypothesis of this Program Project application is that CD results from a abnormality in Innate immune responses to luminal antigens. Our preliminary data suggests that a dysregulation in N0D2 signaling and intestinal permeability may precede the development of chronic ileitis. These effects are associated with abnormal dendritic and macrophage function and excessive activation of the adaptive immune system. The resulting proinflammatory effects leads to the chronic inflammatory response characteristic of CD. The overall objective of this Program Project is to understand the mechanisms of innate immune dysfunction in CD pathogenesis, with the ultimate goal of developing new therapeutic strategies for this devastating disease. The Program Project will be directed by Dr. Pablo Cominelll and will consist of 4 projects and 2 cores. Project 1, headed by Dr. Fabio Cominelli, will test the hypothesis that a deficit in N0D2 signaling and MDP responses is responsible for SAMP CD-like ileitis. Project 2, headed by Dr. Derek Abbott, will focus on the alternative hypothesis that an exaggeration in N0D2 signaling may result in chronic intestinal inflammation. Project 3, headed by Dr. Klaus Ley, will investigate the role of myeloid cells in mediating chronic ileitis. Project 4, headed by Dr. Theresa Pizarro, will study epithelial-immune cell interactions, specifically the interplay between the intestinal epithelium, dendritic cells, and T regulatory cells. These projects are supported by an Administrative Core, which provides administrative support and coordinates the enrichment program. A Mouse/Histology Core will centralize the production and breeding of mice with experimental CD and provide centralized pathologic and histological analysis. The long-term goal of this Program Project is to understand key pathogenic mechanisms of innate immunity in experimental CD, which can be immediately translated to the human condition.